Neuroprotective Role of Hypothermia in Acute Spinal Cord Injury

Even nowadays, the question of whether hypothermia can genuinely be considered therapeutic care for patients with traumatic spinal cord injury (SCI) remains unanswered. Although the mechanisms of hypothermia action are yet to be fully explored, early hypothermia for patients suffering from acute SCI has already been implemented in clinical settings. This article discusses measures for inducing various forms of hypothermia and summarizes several hypotheses describing the likelihood of hypothermia mechanisms of action. We present our objective neuro-electrophysiological results and demonstrate that early hypothermia manifests neuroprotective effects mainly during the first- and second-month post-SCI, depending on the severity of the injury, time of intervening, duration, degree, and modality of inducing hypothermia. Nevertheless, eventually, its beneficial effects gradually but consistently diminish. In addition, we report potential complications and side effects for the administration of general hypothermia with a unique referment to the local hypothermia. We also provide evidence that instead of considering early hypothermia post-SCI a therapeutic approach, it is more a neuroprotective strategy in acute and sub-acute phases of SCI that mostly delay, but not entirely avoid, the natural history of the pathophysiological events. Indeed, the most crucial rationale for inducing early hypothermia is to halt these devastating inflammatory and apoptotic events as early and as much as possible. This, in turn, creates a larger time-window of opportunity for physicians to formulate and administer a well-designed personalized treatment for patients suffering from acute traumatic SCI.

Thermal pharmacology: history and definition

The literature review shows that temperature pharmacology is a new scientific and practical direction of pharmacology, in which the local effect of drugs on individual tissues, organs or parts of the body is realized at a certain local temperature. This trend was formed in Russia at the end of the 20th century due to the fact that such great surgeons as V.A. Negovsky, E.N. Meshalkin and V.I. Shumakov proved in clinical conditions that hypothermia prolongs the safety of the brain, heart and kidneys in the absence of arterial blood and/or oxygen. Then, under the influence of the successful use of local hypothermia for therapeutic purposes in such areas as resuscitation, transplantology and surgical treatment of heart and major vascular diseases, the study of the mechanism of action of local hypothermia as a medicine began. Intensive research in this area began in 1981 at the Department of Pharmacology of the Izhevsk Medical Institute. In the following years, the features of the local action of local hypothermia, drugs and their combinations on mitochondria, blood, blood vessels, myocardium, intestines and limbs of experimental animals and patients in normal conditions, as well as in hypoxia and ischemia were studied. Very soon, the results of research allowed to reveal the main mechanisms of action of local hypothermia and the laws of temperature dependence of the local action of drugs. This allowed to invent several original methods of pharmaco-cold and pharmaco-warm effects that increase the effectiveness of treatment of arterial obstruction of the extremities, inflammatory processes and parenchymal bleeding. It is indicated, that the main provisions of temperature pharmacology were formulated by 1988. The chronology of resolving the contradictions that arose at that time between the widespread public opinion and new ideas about the role of local temperature in the mechanism of local action of drugs in hypoxia, ischemia, inflammation of organs and tissues, and bleeding is shown. Achievements and prospects of development of temperature pharmacology in medicine, biology, pharmacology and pharmacy are shown.

Cytostatic hypothermia and its impact on glioblastoma and survival

Novel therapeutic approaches are needed for patients with recurrent glioblastoma (GBM) who otherwise have limited options. Hypothermia has been used to cryo-ablate tumor locally, but this is ineffective against infiltrative cells as it damages healthy tissue too. Alternatively, here we developed and deployed local ′cytostatic′ hypothermia to stunt GBM growth. We first investigated three grades of hypothermia in vitro and identified a cytostatic window of 20-25°C. We also determined that 18 h/d of cytostatic hypothermia can be sufficient to prevent growth. Cytostatic hypothermia resulted in cell cycle arrest, reduced metabolite production and consumption, and reduced inflammatory cytokine synthesis. We designed a device to deliver local cytostatic hypothermia in vivo in two rodent models of GBM: utilizing the rat F98 and the human U-87 MG lines. Local hypothermia more than doubled the median survival of F98 bearing rats from 3.9 weeks to 9.7 weeks. Two rats survived through 12 weeks. No loss of U-87 MG bearing rats was observed during their study period of 9 weeks. Additionally, we demonstrated that cytostatic hypothermia is synergistic with chemotherapy in vitro. Interestingly, we also demonstrate that CAR T immunotherapy can function with cytostatic hypothermia. Unlike modern targeted therapeutics, cytostatic hypothermia affects multiple cellular processes simultaneously. Thus, irrespective of the host species (e.g., rodent vs. human), it could slow tumor progression and the evolution of resistance. Our studies show that this approach enhances progression-free survival without chemical interventions. However, it may also provide time and opportunities to use standard concomitant, adjuvant, and novel cytotoxic treatments. For these reasons, local cytostatic hypothermia could be a critical addition to the limited options patients with GBM have.

Measurement of the Intracochlear Hypothermia Distribution Utilizing Tympanic Cavity Hypothermic Rinsing Technique in a Cochlea Hypothermia Model

Introduction: Cochlea implants can cause severe trauma leading to intracochlear apoptosis, fibrosis, and eventually to loss of residual hearing. Mild hypothermia has been shown to reduce toxic or mechanical noxious effects, which can result in inflammation and subsequent hearing loss. This paper evaluates the usability of standard surgical otologic rinsing as cooling medium during cochlea implantation as a potential hearing preservation technique.Material and Methods: Three human temporal bones were prepared following standard mastoidectomy and posterior tympanotomy. Applying a retrocochlear approach leaving the mastoidectomy side intact, temperature probes were placed into the basal turn (n = 4), the middle turn (n = 2), the helicotrema, and the modiolus. Temperature probe positions were visualized by microcomputed tomography (μCT) imaging and manually segmented using Amira® 7.6. Through the posterior tympanotomy, the tympanic cavity was rinsed at 37°C in the control group, at room temperature (in the range between 22 and 24°C), and at iced water conditions. Temperature changes were measured in the preheated temporal bone. In each temperature model, rinsing was done for 20 min at the pre-specified temperatures measured in 0.5-s intervals. At least five repetitions were performed. Data were statistically analyzed using pairwise t-tests with Bonferroni correction.Results: Steady-state conditions achieved in all three different temperature ranges were compared in periods between 150 and 300 s. Temperature in the inner ear started dropping within the initial 150 s. Temperature probes placed at basal turn, the helicotrema, and middle turn detected statistically significant fall in temperature levels following body temperature rinses. Irrigation at iced conditions lead to the most significant temperature drops. The curves during all measurements remained stable with 37°C rinses.Conclusion: Therapeutic hypothermia is achieved with standard surgical irrigation fluid, and temperature gradients are seen along the cochlea. Rinsing of 120 s duration results in a therapeutic local hypothermia throughout the cochlea. This otoprotective procedure can be easily realized in clinical practice.

An injectable refrigerated hydrogel for Inducing local hypothermia and neuroprotection against traumatic brain injury

Hypothermia is a promising therapy for Traumatic brain injury (TBI) in the clinic. However, the neuroprotective outcomes of hypothermia-treated TBI are not consistent in clinical studies due to several severe side effects. Here, an injectable refrigerated hydrogel is designed to deliver 3-iodothyronamine (T1AM) to achieve a longer period of local hypothermia for TBI treatment. The hydrogel has four advantages: (1) It can be injected into injured site after TBI, where it forms a hydrogel and avoids the side effects of whole-body cooling. (2) The hydrogel can biodegrade and be used for controlled drug release. (3) Released T1AM can bind to trace amine-associated receptor 1 (TAAR1) to produce cyclic adenosine monophosphate (cAMP), which induces hypothermia. (4) This hydrogel has an increased medical value due to its simple operation and ability to achieve timely treatment. This hydrogel is able to cool the brain to 30.25 ± 2.25 °C for 12 hours while maintaining the body temperature at 36.80 ± 1.75 °C after TBI. More importantly, the hypothermia induced by this hydrogel leads to the maintenance of blood-brain barrier (BBB) integrity, the prevention of cell death, the reduction of the inflammatory response and brain edema, and the promotion of functional recovery after TBI. This cooling method can potentially be developed as a new approach for hypothermia treatment in TBI.

Dynamics of intraocular temperature during local hypothermia (experimental study and mathematical modeling)

Therapeutic hypothermia currently is successfully in various fields of medicine to protect biological tissues from ischemia. However the issue of changes in intraocular temperature under hypothermia remains poorly understood. Purpose. To study the dynamics of intraocular temperature in conditions of local hypothermia and on the basis of the obtained data to develop a mathematical model of thermophysical processes in the rabbit eye. Materials and methods. An in vivo experiment was performed on 10 rabbits (20 eyes). In group 1 (5 rabbits, 10 eyes), epibulbar and intraocular temperature was measured after local contact hypothermia through closed eyelids, in group 2 (5 rabbits, 10 eyes) after local contact hypothermia directly through the cornea. ока безпосередньо через рогівку. Для гіпотермії застосовувався гелевий акумулятор холоду температурою -10 °С. Для вимірювання температури в різних відділах ока застосовувався термоелектричний пристрій, розроблений Інститутом термоелектрики НАН і МОН України та ДУ «Інститут очних хвороб і тканинної терапії ім. В. П.Філатова НАМН України». Для розробки математичної моделі теплофізичних процесів в оці кролика використано пакет прикладних програм COMSOL Multiphysics. Результати. Температура склоподібного тіла в 1-й і 2-й групі тварин знизилася в порівнянні з вихідними даними відповідно на 2,8 °С і 5,4 °С. Температурний градієнт між зовнішньою поверхнею рогівки і середньою частиною склоподібного тіла ока кролика в 1-й групі становив 7,1 °С, у 2-й групі – 9,2 °С. На підставі отриманих експериментальних даних було розроблено схематичну, математичну та комп’ютерну моделі ока кролика з урахуванням його теплофізичних особливостей, кровообігу, процесів метаболізму і теплообміну. Висновки. У разі локальної контактної гіпотермії очей кролика відбувається зниження епібульбарної температури і температури внутрішньоочних середовищ, як під час охолодження безпосередньо зовнішньої поверхні рогівки, так і під час впливу холоду через закриті повіки. Ключові слова: внутрішньоочна температура, локальна гіпотермія, око кролика, математична модель ока. Для цитування: Анатичук ЛІ, Пасєчнікова НВ, Науменко ВО, Задорожний ОС, Назаретян РЕ, Кобилянський РР, Верешко ЄЮ. Динаміка внутрішньоочної температури в умовах локальної гіпотермії (експериментальне дослідження та математичне моделювання). Журнал Національної академії медичних наук України. 2019;25(4):383–8

Potential for the application of dynamic skin thermography after local hypothermia

Infrared thermography is one of the widely used non-invasive diagnostic methods. While the procedure is mainly used for early malignant tumor diagnostics, a potential application for thermography was proposed in cardiovascular, skin, autoimmune diseases, arthritis, Reynaud’s syndrome, burns, surgery and therapeutic treatment monitoring. The method of thermographic evaluation has not changed significantly since the end of 20th century. In this study we attempted to characterize the influence of skin capillary blood flow on surface temperature recuperation following local hypothermia. To improve sensitivity and standardize the procedure we developed a study protocol that involves minimizing or excluding the influence of external factors on study results. An original applicator was used to apply dosed hypothermia. Massive porcine tissue block was chosen as a passive model without active heat and mass transfer but with heat capacity, structure and heat dissipation characteristics similar to human tissues. 51 healthy volunteers were assigned to control group, while 16 patients with diabetes mellitus constituted the main study group. Cumulative temperature difference was calculated in all cases. It was 121,8 ± 70,8 °С×s in the control group, 95,6 ± 54,4 °С×s in the main study group and 307,2 ± 43,4 °С×s in the passive model. Based on the study results, we made the following conclusions: absence of heat and mass transfer in the passive model complicates heat balance recuperation due to layered structure of the skin; heat balance recuperation curve is an individual parameter and is not influenced by age or gender.